PROJECT SUMMARY/ABSTRACT We recently used the Cre/loxP system to selectively delete dopamine D1 receptors from GABAergic neurons from the Nkx2.1 lineage within the medial ganglionic eminence. These cells largely produce a subset of crucial cerebral cortical interneurons within the medial frontal cortex. Although these interneuron-localized receptors represent just a small fraction of cortical dopamine D1 receptors (most are on excitatory glutamatergic projection neurons), these conditional knockout mice exhibit a remarkable phenotype in one functional domain ? mood. Specifically, GABA-D1-cKO mice exhibit decreased immobility in the forced swim test, and decreased latency to consume a palatable liquid in a novel stressful environment; these are both indicative of an antidepressant-like effect. These data suggest a new mechanism by which cerebral cortical interneurons may contribute to mood regulation, and importantly, this mechanism may be ?druggable?. The current proposal seeks to validate this model using additional behavioral measures and stressors (Aim 1), define the developmental timing components of this neuroadaptation (Aim 2), and begin to assess the cellular and molecular underpinnings of this response (Aim 3). Success of this current project will position us to subsequently develop unique therapeutic strategies to selectively manipulate these receptors through genetic and pharmacological approaches that are limited to specific neuronal subpopulations.